Freeze-drying, also known as lyophilization, is a process for drying high-quality products such as, for example, pharmaceuticals, biological materials such as proteins, enzymes, microorganisms, and in general any thermo- and/or hydrolysis-sensitive material. Freeze-drying provides for the drying of the target product via the sublimation of ice crystals into water vapor, i.e., via the direct transition of water content from the solid phase into the gas phase. Freeze-drying is often performed under vacuum conditions, but works generally also under atmospheric pressure.
In the fields of pharmaceuticals and biopharmaceuticals freeze-drying processes may be used, for example, for the drying of drug formulations, Active Pharmaceutical Ingredients (“APIs”), hormones, peptide-based hormones, monoclonal antibodies, blood plasma products or derivatives thereof, immunological compositions including vaccines, therapeutics, other injectables, and in general substances which otherwise would not be stable over a desired time span. In freeze-dried products the water and/or other volatile substances are removed prior to sealing the product in vials or other containers. In the fields pharmaceuticals and biopharmaceuticals the target products are typically packaged in a manner to preserve sterility and/or containment. The dried product may later be reconstituted by dissolving it in an appropriate reconstituting medium (e.g., sterile water or other pharmaceutical grade diluents) prior to use or administration.
Design principles for freeze-dryer devices are known. For example, tray-based freeze-dryers comprise one or more trays or shelves within a (vacuum) drying chamber. Vials can be filled with the product and arranged on a tray. The tray with the filled vials is introduced into the freeze-dryer and the drying process is started.
Process systems combining spray-freezing and freeze-drying are also known. For instance, U.S. Pat. No. 3,601,901 describes a highly integrated device comprising a vacuum chamber with a freezing compartment and a drying compartment. The freezing compartment comprises a spray nozzle on top of an upwardly projecting portion of the vacuum chamber. The sprayed liquid is atomized and rapidly frozen into a number of small frozen particles which fall down within the freezing compartment to arrive at a conveyor assembly. The conveyor advances the particles progressively for freeze-drying in the drying compartment. When the particles reach the discharge end of the conveyer, they are in freeze-dried form and fall downwardly into a discharge hopper.
In another example, WO 2005/105253 describes a freeze-drying apparatus for fruit juices, pharmaceuticals, nutraceuticals, teas, and coffees. A liquid substance is atomized through a high-pressure nozzle into a freezing chamber wherein the substance is cooled to below its eutectic temperature, thereby inducing a phase change of liquids in the substance. A co-current flow of cold air freezes the droplets. The frozen droplets are then pneumatically conveyed by the cold air stream via a vacuum lock into a vacuum drying chamber and are further subjected to an energy source therein to assist sublimation of liquids as the substance is conveyed through the chamber.
Many products are compositions comprising two or more different agents or components that are mixed prior to freeze-drying. The composition is mixed with a predefined ratio and is then freeze-dried and filled into vials for shipping. A change in the mixing ratio of the composition after filling into the vials is practically not feasible. In typically freeze-drying procedures the mixing, filling, and drying processes cannot normally be separated.
WO 2009/109550 A1 discloses a process for stabilizing a vaccine composition containing an adjuvant . It is proposed to separate, if desirable, the drying of the antigen from the drying of the adjuvant, followed by blending of the two components before combined filling or to employ sequential filling of the respective components. Specifically, separate micropellets comprising either the antigen or the adjuvant are generated. The antigen micropelets and the adjuvant micropellets are then blended before filling into vials, or are directly filled to achieve the desired mixing ratio specifically at the time of blending or filling. The methods are said to further provide be an improvement in the composition's overall stability, as the formulations can be optimized independently for each component. The separated solid states are said to avoid interactions between the different components throughout storage, even at higher temperature.
Products in the pharmaceutical and biopharmaceutical fields often have to be manufactured under closed conditions, i.e., they have to be manufactured under sterile conditions and/or under containment. A process line adapted for a production under sterile conditions has to be designed such that no contaminates can enter into the product. Similarly, a process line adapted for production under containment conditions has to be adapted such that neither the product, elements thereof, nor auxiliary materials can leave the process line and enter the environment.
Two approaches are known for the engineering of process lines adapted for production under closed conditions. The first approach comprises placing the entire process line or parts/devices thereof into at least one isolator, the latter being a device isolating its interior and the environment from each other and maintaining defined conditions inside. The second approach comprises developing an integrated process system providing for sterility and/or containment, which is usually achieved by integrating within one housing a device which is specifically adapted and highly integrated to perform all the desired process functions.
As an example for the first approach, WO 2006/008006 A1 describes a process for the sterile freezing, freeze-drying, storing, and assaying of a pelletized product. The process comprises freezing droplets of the product to form pellets, freeze-drying the pellets, then assaying and loading the product into containers. More particularly, the frozen pellets are created in a freezing tunnel and then they are directed into a drying chamber, wherein the pellets are freeze-dried on a plurality of pellet-carrying surfaces. After freeze-drying, the pellets are unloaded into storage containers. The process of pelletizing and freeze-drying is performed in a sterile area implemented inside an isolator. Filled storage containers are transferred into a storage assay. For final filling, storage containers are transferred into another sterile isolator area containing a filling line, where the containers' contents are transferred to vials, these being sealed after filling and finally unloaded from the isolated filling line.
Putting a process line into a box, i.e., into one or more isolators, appears to be a straight-forward approach for ensuring sterile production. However, such systems and the operation thereof become increasingly complex and costly with increasing size of the processes and correspondingly increasing size of the required isolator(s). Cleaning and sterilization of these systems requires not only the process line to be cleaned and sterilized after each production run, but also the isolator. In cases where two or more isolators are required, interfaces between the isolated areas occur that require additional efforts for protecting the sterility of the product. At some point, process devices and/or isolators can no longer be realized from standard devices and have to be specifically developed further increasing complexity and costs.
An example of the second approach to providing process lines for production under closed conditions, namely providing a specifically adapted and highly integrated system, is given by the above-mentioned U.S. Pat. No. 3,601,901. According to the '901 patent a freezing compartment and a drying compartment are formed within a single vacuum chamber. Such an approach generally excludes the use of standard devices, i.e., the process equipment is per se costly. Further, due to the highly integrated implementation of the various process functions normally the entire system is in one particular mode, for example in a production run, or in a maintenance mode such as cleaning or sterilization which limits the flexibility of the process line.